Low back pain is a major clinical problem second only to the common cold in its financial and symptomatic impact on human suffering. Our long-term objective is to understand the pathophysiological mechanisms of low back pain associated with lumbar radiculopathy. To achieve this goal, we will apply experience with animal models of lumbar radiculopathy and chronic neuropathic pain to evaluate and test our hypothesis. In the current proposal, we apply data from the previous funding period to investigate the following hypothesis: Lumbar nerve root injury produces a CNS immune mediator imbalance, which leads to an "autoimmune" syndrome that in turn manifests as persistent radicular pain. The research proposed in the present application, when integrated with our previous data, will determine the individual roles and the collective interactions of specific cytokines and chemotaxic cytokines, (chemokines) and cell trafficking in the etiology of persistent radicular pain. The central hypothesis will be tested by using established methods in our laboratory to investigate the following Specific Aims: 1. Assess the role of chemokines in the etiology of persistent radicular pain using the Chromic Lumbar Radiculopathy (C-LR) rodent model. 2. Continue to address importance of site of injury in relationship to the DRG to pain generation. 3. Determine whether cells traffic from the periphery into the central nervous system in response to lumbar nerve root injury that results in persistent radicular pain. 4. Assess the contribution of mechanical root injury versus chemical inflammatory components in the generation of radicular pain. 5. Determine the effect of selective and global immunosuppressive therapy on the potential to alter sensory processing and on the central inflammatory cascade. When completed, this project will provide: Information on the in vivo kinetics of spinal proinflammatory cytokine and chemokine expression and production in a rodent radiculopathy models; Preliminary data to guide and support new pharmacological treatments of acute and chronic low back pain; New insight into the relationship between the neuroimmune response of nerve root injury and the clinical phenomenon of low back pain; Preliminary data to direct future studies that evaluate the impact of central neuroimmune activation in causation of low back pain with radiculopathy; New information on the pathogenetic distinction between nerve injury central or peripheral to the dorsal root ganglion (a clinically relevant anatomical location). This new knowledge will guide development of novel, non-addictive preventive therapies and treatments for chronic low back pain.